An organisms major histocompatibility complex defines a set of cell surface molecules which are very important in the discrimination between self and non-self. Indeed, the MHC gene products are intimately involved in the interactions between T cells, B cells, and macrophages, which reglate both the cellular and humoral phases of the immune response. The research described in this proposal is designed to take advantage of the availability of certain strains of mice with mutations in their MHC genes, which cause altered 'reactivities' in a variety of immunological assays, to study the correlation between specific structural changes in the gene products of the Class I regions of the murine MHC (H-2) and alterations immunological reactivity (function). The mutant and parental hisocompatibility antigens (H-2 molecules) will be isolated by specific immunoprecipitation from radiolabeled cells. The location and precise nature of the amino acid changes in the H-2 molecules from the cells of the mutant strain will be determined by preparing appropriate fragments of the molecules e.g. CNBr fragments, and comparing their structure to that of fragments of the H-2 gene products from the non-mutant strain by peptide-mapping. Radiochemical microsequence analyses of appropriate peptides will be used to determine the exact amino acid differences from the non-mutant molecule in the H-2 molecule from the mutant strain. The long term objective of this work is the precise correlation of the structure and function at the lymphocyte cell surface. Since the immune system has an extraordinary predilection for the MHC gene products, and uses recognition of these cell surface molecules to control cell-cell communication in the immune system, the work proposed here has relevance to general immunobiology as well as to molecular immunology and our understanding of the biochemistry of cell surface membrane molecules. Studies of molecules that regulate the functining of the immune system have obvious health-relatedness. Although the work proposed here is in the mouse, the MHC's of man and the mouse have very similar genetic organizations, and control similar if not identical functions. The results of studies of the murine MHC have and will probably continue to have a direct relationship to our understanding of the MHC of man.